Folic Acid, BH4 and Neopterin

Author: Gianpiero Pescarmona
Date: 25/07/2007


Tetrahydrofolate (THF) is the combination of a pterin ring, p-aminobenzoate and glutamate (possibly multiple glutamate units. The initial product is folate, which has the second ring fully desaturated. This is reduced by dihydrofolate reductase by two moles of NADPH, first to dihydrofolate, and finally to tetrahydrofolate, THF.

Levomefolic Acid


Methionine is necessary for synthesis of:

  • Carnitine

more details

FIG. 3. Box plots demonstrating relative levels of metabolites. (A) methionine metabolism; (B) glutathione metabolism. © Box plots of serum taurine and glycine. (D) qRT-PCR of hepatic mRNA expression of genes related to methionine metabolism, trans-sulfuration, and DNA methylation pathway in controls (n = 10, in duplicate) and those with ALD (n = 30). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (E) Schematic diagram illustrating the methionine metabolism pathway. (F) Hepatic taurine and glycine concentration from controls (n = 12) and from those with ALD (n = 30). Abbreviations: AHCY, adenosylhomocysteinase; BHMT1, betainehomocysteine S-methyltransferase 1; CBS, cystathionine-beta-synthase; CDO1, cysteine dioxygenase type 1; CTH, cystathionine gamma-lyase; DNMT, DNA methyltransferase; GNMT, glycine N-methyltransferase; MTHFR, methylenetetrahydrofolate reductase; N5-MTHF, N5-methyltetrahydrofolate; PEMT, phosphatidylethanolamine methyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahydrofolate.
Serum Metabolomic Profiling Identifies Key Metabolic Signatures Associated With Pathogenesis of Alcoholic Liver Disease in Humans, 2019

Linus Pauling Center: Folate

C1 metabolism short

Folate coenzymes

Folic acid nomenclature and symbols

MethylTHF is essential for all methylation reactions including Choline synthesis

BH4 synthesis from GTP

BH2 reduction to BH4

Open Questions

Folati connessi a performance cognitiva
Sussiste un'associazione fra elevate concentrazioni plasmatiche di folati ed una migliore performance cognitiva, a prescindere dalla concentrazione di omocisteina. Con l'incremento della concentrazione di folati si osserva una significativa diminuzione del volume delle lesioni della materia bianca (WML) e del numero di lesioni gravi. Dato che le WML preventricolari e subcorticali sono in genere considerate marcatori di patologie microvascolari cerebrali, e la perdita di volume ippocampale ed amigdalare indicatori precoci di morbo di Alzheimer, i dati del presente studio suggeriscono che lo status relativo ai folati sia correlato alla sfera cognitiva tramite meccanismi vascolari piuttosto che con un processo neurodegenerativo primario. (Am J Clin Nutr 2007; 86: 728-34)

Folates and thymidine synthesis

Folic Acid Supplementation

ISS - Istituto Superiore di Sanita'
Acido Folico per la Prevenzione Primaria di Difetti Congeniti
A Livello Nazionale ed Internazionale e' Ormai Riconosciuto il Ruolo dell'Acido
Folico nella Prevenzione di Alcuni Difetti Congeniti. Le Maggiori Organizzazioni
Scientifiche che si Occupano di Prevenzione e Protezione della Salute sono
Impegnate nella Valutazione Attenta del Rapporto Rischio-Beneficio e della
Efficacia delle Diverse Strategie Attuabili Utili a Coprire il Fabbisogno di Questa
Vitamina nella Popolazione Generale e Soprattutto nelle Donne in Eta' Fertile
Queste Valutazioni Rappresentano un Elemento Fondamentale ed
Irrinunciabile Affinche' le Istituzioni Possano Attuare Decisioni in Materia
Il Documento Contiene i Riassunti del Convegno del Network Italiano Acido
Folico che si Terra' a Roma il 09 Ottobre 2009

Folic Acid Supplementation and embryo selection

The balance between the use of methylene-H4 folate for DNA synthesis rather than for methionine synthesis might depend on the presence of the 677T variant of methylenetetrahydrofolate reductase (MTHFR) and the nutritional folate status. Given adequate dietary folate, the 677T variant of MTHFR functions as a 'valve', preferentially routing one-carbon units to DNA at the expense of methionine. If folate nutritional status is poor, the 677T variant might promote the misincorporation of uracil into DNA, leading to chromosome breakage. This mechanism might therefore select embryos that are best suited to reproductive success for a given environmental abundance of dietary folate by augmenting dTMP (deoxythymidine monophosphate) synthesis. Therefore, given the current practice of increasing dietary folate before conception, in utero selection of the 677T variant might lead to a negative, long-term effect on the prevalence of cancer and vascular disease for which this mutation is a potential risk factor.

from Folic acid — vitamin and panacea or genetic time bomb? 2005

BH4/folate interactions

Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent 2007

fig. 5


Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs

2010-03-26T22:47:35 - silvia marola

Stahl papers

BH4 is a basic cofactor involved in norephinefrine and serotonine synthesis.

Deficit of norephinefrine and serotonine play a major role in pathogenesis of Major Depressive Disease that is a leading cause of disability worldwide.
Nowadays therapies of MDD are based on administration of SSRI and SNRI.
We decided to investigate the biosynthetic pathway of BH4.
We focused on 2 enzimes:
MTHFR that convert directy BH2 in BH4 with NADPH as donor of H
DHFR that convert directy BH2 in BH4 with THF as donor of H
(as shown in the first picture).

So could be really interesting evaluate if folic acid therapy could be useful in treatment of MDD patient. Nowadays no trials have been able to show that the supplementation of folate benefits depressive symptoms.
There is an new Australian trials (2010 january) that will pursuit this target!!!!!
The B-VITAGE trial: A randomized trial of homocysteine lowering treatment of depression in later life

(for the other reference, click here)

Endoplasmic reticulum stress increases the expression of methylenetetrahydrofolate reductase through the IRE1 transducer. 2008

  • Abstract
    Methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate and homocysteine metabolism, influences many cellular processes including methionine and nucleotide synthesis, methylation reactions, and maintenance of homocysteine at nontoxic levels. Mild deficiency of MTHFR is common in many populations and modifies risk for several complex traits including vascular disease, birth defects, and cancer. We recently demonstrated that MTHFR can be up-regulated by NF-kappaB, an important mediator of cell survival that is activated by endoplasmic reticulum (ER) stress. This observation, coupled with the reports that homocysteine can induce ER stress, prompted us to examine the possible regulation of MTHFR by ER stress. We found that several well characterized stress inducers (tunicamycin, thapsigargin, and A23187) as well as homocysteine could increase Mthfr mRNA and protein in Neuro-2a cells. The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression, whereas a reported inhibitor of c-Jun (SP600125) and a dominant-negative derivative of c-Jun N-terminal kinase-1 reduced MTHFR activation. We conclude that ER stress increases MTHFR expression and that IRE1 and c-Jun mediate this activation. These findings provide a novel mechanism by which the ER can regulate homeostasis and allude to an important role for MTHFR in cell survival.
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